Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]3[C:15](=[O:29])[N:16]([CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)[N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ca+2].[Br-:35].[Br-].[Br-].C[N+](C)(C)CC1C=CC=CC=1.C[N+](C)(C)CC1C=CC=CC=1.C[N+](C)(C)CC1C=CC=CC=1>ClCCl.CO>[Br:35][C:9]1[C:10]2[N:11]([C:15](=[O:29])[N:16]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=3)[N:17]=2)[C:12]([CH3:14])=[N:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2ccc(Cl)cc2)c(Br)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 60 °C
Yield: 109.5 %

Procedure:
To a solution of 7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (210 mg, 0.50 mmol) in dichloromethane (10 mL) and methanol (10 mL) at room temperature under argon was added calcium carbonate (50.0 mg, 0.50 mmol) and N,N,N-trimethyl-1-phenylmethanaminium tribromide (195 mg, 0.50 mmol). The resulting suspension was stirred and heated at 60° C. under argon for 1 h. Analysis by HPLC/MS indicated that the starting material had been consumed. The solvents were removed under reduced pressure, and water (25 mL) was added. After stirring at room temperature for 30 min, the solid product was collected by filtration and further washed with water (2×10 mL). After drying, the title compound (273 mg) was obtained as an off-white solid. HPLC/MS: retention time=3.84 min, [M+H]30 =500.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].[Br:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[BrH:9].[CH3:1][C:2]1[N:3]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[NH:8])[S:5][C:6]=1[CH3:7]
Reactant: BrCCOc1ccccc1
Reactant: Cc1nc(N)sc1C
Product: Br
Product: Cc1sc(=N)n(CCOc2ccccc2)c1C
Temperature: 85 °C
Yield: 50.6 %

Procedure:
A mixture of 4,5-dimethylthiazol-2-ylamine (1.0 g, 7.8 mmol) and (2-bromo-ethoxy)benzene (1.9 g, 9.4 mmol) were heated neat to 85° C. for 19 hours. The mixture was cooled to ambient temperature and the residue was crystallized from isopropanol. The solid was collected by filtration and dried under vacuum to afford 1.3 g (50%) of the title compound. MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]([F:27])([F:26])[C:15]1[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.Br.[Cl:39][C:40]1[C:49]([OH:50])=[C:48]([OH:51])[C:47]([Cl:52])=[C:46]2[C:41]=1[CH2:42][CH2:43][NH:44][CH2:45]2>CCOC(C)=O.O>[Cl:39][C:40]1[C:49]([OH:50])=[C:48]([OH:51])[C:47]([Cl:52])=[C:46]2[C:41]=1[CH2:42][CH2:43][N:44]([C:23](=[O:25])/[CH:22]=[CH:21]/[C:18]1[CH:19]=[N:20][C:15]([C:14]([F:13])([F:27])[F:26])=[CH:16][CH:17]=1)[CH2:45]2
Reactant: Oc1c(O)c(Cl)c2c(c1Cl)CCNC2
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)nc1
Agent: Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1ccc(C(F)(F)F)nc1)N1CCc2c(Cl)c(O)c(O)c(Cl)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of CDI (83 mg, 0.51 mmol) in EtOAc (2 mL) was added (E)-3-(6-(trifluoromethyl)pyridin-3-yl)acrylic acid (100 mg, 0.46 mmol). The resulting mixture was heated at reflux for 1 h after which HOBt (35 mg, 0.23 mmol) and 5,8-dichloro-1,2,3,4-tetrahydroisoquinoline-6,7-diol hydro bromide (145 mg, 0.46 mmol) were added. Heating at reflux was continued for 3 h before the reaction mixture was allowed to cool to rt. It was then poured into water (15 mL) and the water-phase was extracted with EtOAc (3×15 mL). Combined organics were washed with water (10 mL) and brine (10 mL) and dried (MgSO4). After filtration and evaporation, the crude was purified by column chromatography (SiO2, EtOAc:petroleum ether 50:50) to give a bright yellow solid which was purified further by precipitating the product in EtOAc via addition of petroleum ether. After decantation of the solvent and drying, the title compound (110 mg, 0.25 mmol, 55%) was obtained as a light reddish solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl.[CH3:5][NH:6][CH3:7].[C:8]1([C:14]2[N:15]=[C:16]([CH:19]=O)[S:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.CO>[CH3:5][N:6]([CH3:7])[CH:19]([C:16]1[S:17][CH:18]=[C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:15]=1)[C:1]#[N:2]
Reactant: CNC
Reactant: [C-]#N
Reactant: O=Cc1nc(-c2ccccc2)cs1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)C(C#N)c1nc(-c2ccccc2)cs1
Temperature: -25 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
Sodium cyanide (124 mg, 2.53 mmol) was added to a solution of dimethylamine hydrochloride (280 mg, 3.43 mmol) in water (10 mL), followed by the addition of a solution of 4-phenylthiazole-2-carbaldehyde (400 mg, 2.11 mmol) in methanol (20 mL) while maintaining the temperature at −25° C. The reaction mixture was further stirred for 4 h at same temperature, then it was diluted with water and the organic product was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to get the crude product, which was purified by column chromatography (silica 60-120 mesh, eluant 15% EtOAc in petroleum ether), to yield 2-(dimethylamino)-2-(4-phenylthiazol-2-yl)acetonitrile (160 mg, yield 31%). 1H NMR (400 MHz, CDCl3) δ 7.97-7.94 (m, 2H), 7.57 (s, 1H), 7.46-7.42 (m, 2H), 7.38-7.33 (m, 1H), 5.12 (s, 1H), 2.50 (s, 6H). MS (ESI) m/z: Calculated for C13H13N3S: 243.08. found: 244.2 (M+H)+.
Reaction SMILES: C(OC(F)(F)C(F)(F)C(F)(F)F)=C.[C:14]([O:24][CH:25]([C:27]([O:29]C)=[O:28])[F:26])([C:17]([C:20]([F:23])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15].[NH3:31]>>[C:20]([C:17]([C:14]([O:24][CH:25]([C:27]([O-:29])=[O:28])[F:26])([F:15])[F:16])([F:19])[F:18])([F:23])([F:22])[F:21].[NH4+:31]
Reactant: COC(=O)C(F)OC(F)(F)C(F)(F)C(F)(F)F
Reactant: N
Agent: C=COC(F)(F)C(F)(F)C(F)(F)F
Product: O=C([O-])C(F)OC(F)(F)C(F)(F)C(F)(F)F
Product: [NH4+]

Procedure:
A 2 liter glass flask equipped with a mechanical stirrer, thermometer and reflux condenser (−80° C.) is used. Heating of the flask is provided by an electric heating mantle. The conversion is carried out as a one pot reaction. 275 g perfluoropropyl vinyl ether (PPVE), 280 g KOH, 602 g water, 151 g t-butanol, and 10 g methyl trioctyl ammonium chloride are placed in the flask. The three phase mixture is subjected to vigorous stirring. After initial heating a moderate exothermic reaction occours. Mixing is continued for nine hours. During this time the internal temperature adjusts to 27-33° C. Mixing is stopped when the exothermic reaction ceases. The reaction mixture forms two layers. The low temperature reflux condenser is replaced by a standard reflux condenser. Sulfuric acid (392 g) is slowly added without external cooling. The batch is heated to reflux. Unreacted PPVE is vented. At about 80° C. internal temperature gas begins to evolve. Heating is continued until the gas evolution has ceased. At this time the internal temperature reaches 101° C. The batch is cooled to RT and the reflux condenser is replaced by a distillation device. No column is used. 110 g methanol is added to the batch and distillation is started. The condensed vapors form two layers. The lower layer is separated and the upper layer is returned to the flask. Distillation is stopped when no more lower phase is formed. In total, 234 g of lower phase are collected. Fractionation of the lower phase yields 167 g of C3F7OCHFCOOCH3 with a boiling point of 120-122° C. at ambient pressure. Calculated yield: 59% based on total PPVE used; 70% based on converted PPVE. The ester is converted to the ammonium salt by reaction with aqueous ammonia. Methanol is removed by fractionated distillation. The resulting aqueous solution is used as an emulsifier in the polymerization of fluorinated olefins.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:34])([CH3:33])[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH3:33][C:19]([NH:34][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:18])[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]
Reactant: Cc1oc(-c2ccccc2)nc1CC(C)(C)N
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: Cc1oc(-c2ccccc2)nc1CC(C)(C)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 1,1-dimethyl-2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamine (57.2 mg, 0.32 mmol) as starting materials and isolated (75 mg, 73.6%) as white solid; LC-MS (UV peak area, ESI) 92.82%, 446.8 (M+H)+.
Reaction SMILES: [CH:1]1([C:4](=[O:25])[CH:5]([C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])C(OC(C)(C)C)=O)[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:25])[CH2:5][C:13]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])=[O:24])[CH2:3][CH2:2]1
Reactant: COc1cc(SC)ccc1C(=O)C(C(=O)OC(C)(C)C)C(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(SC)ccc1C(=O)CC(=O)C1CC1
Yield: 101.3 %

Procedure:
A solution of t-butyl 3-cyclopropyl-2-(2-methoxy-4-methylsulphenylbenzoyl)-3-oxopropionate (35.1 g) and 4-toluenesulphonic acid (1.2 g) in toluene was stirred and heated at reflux for 8 hours. After cooling, it was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 3-cyclopropyl-1-(2-methoxy-4-methylsulphenylphenyl)-propan-1,3-dione (25.8 g) as a red solid, NMR (CDCl3); 0.7-1.2 (m,4H), 1.4-2.0 (m,1H), 2.4(s,3H), 3.75 (s,3H), 6.4(s,1H), 6.6(s,1H), 6.65 (d,1H) and 7.65 (d,1H).
Reaction SMILES: [N+](C1C=CC(C(OO)=O)=CC=1)([O-])=[O:2].C(O)(C)(C)C.[C:19]([O:22][C:23]1[CH:41]=[CH:40][C:39]2[C@@H:38]3[C@H:28]([C@H:29]4[C@@:33]([CH2:36][CH2:37]3)([CH2:34][CH3:35])[CH:32]=[CH:31][CH2:30]4)[CH2:27][CH2:26][C:25]=2[CH:24]=1)(=[O:21])[CH3:20]>C(Cl)CCl>[C:19]([O:22][C:23]1[CH:41]=[CH:40][C:39]2[C@@H:38]3[C@H:28]([C@H:29]4[C@@:33]([CH2:36][CH2:37]3)([CH2:34][CH3:35])[C@@H:32]3[O:2][C@@H:31]3[CH2:30]4)[CH2:27][CH2:26][C:25]=2[CH:24]=1)(=[O:21])[CH3:20]
Reactant: CC[C@@]12C=CC[C@H]1[C@@H]1CCc3cc(OC(C)=O)ccc3[C@H]1CC2
Reactant: O=C(OO)c1ccc([N+](=O)[O-])cc1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: CC[C@]12CC[C@@H]3c4ccc(OC(C)=O)cc4CC[C@H]3[C@@H]1C[C@H]1O[C@H]12
Reaction time: 18 h

Procedure:
At room temperature, a solution of 460 mg. of p-nitroperbenzoic acid in 3 ml. of tert.-butanol and 0.6 ml. of ethylene chloride is gradually added to 600 mg. of 3-acetoxy-18-methyl-1,3,5(10),16-estratetraene in 20 ml. of ethylene chloride. After 18 hours, the crude product is worked up as described in (A) and purified by preparative layer chromatography (eluent: hexane/ethyl acetate = 7 : 3). In this way, 490mg. of 3-acetoxy-16α,17α-epoxy-18-methyl-1,3,5(10)-estratriene is isolated as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([O:14]CC)=[O:13])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCC(CC(=O)OCC)Cc1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(CC(=O)O)Cc1cccc(OC)c1
Yield: 99 %

Procedure:
Ethyl ester 91 (3.12 g, 11.8 mmol) was saponified with 1 N NaOH in THF and EtOH to give 2.76 g (99%) of the title compound (92) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.87 (t, J=6.8 Hz, 3H), 1.25-1.45 (m, 4H), 2.10-2.22 (m, 1H), 2.25-2.30 (m, 2H), 2.50-2.60 (m, 1H), 2.65-2.75 (m, 1H), 3.79 (s, 3H), 6.70-6.80 (m, 3H), 7.19 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl.O>[CH3:28][C:27]([Si:24]([CH3:26])([CH3:25])[N:4]1[CH2:5][CH2:6][CH:2]([CH3:1])[C:3]1=[O:7])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1CCNC1=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1CCN([Si](C)(C)C(C)(C)C)C1=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
In an oven-dried 500 ml flask under argon was dissolved 3-methyl-2-pyrrolidinone (0.186 mol, 18.4 g) in 200 ml methylene chloride. To this solution was added Triethylamine (0.223 mol, 22.6 g), Dimethylaminopyridine (0.019 mol, 2.27 g), and t-Butyldimethylsilyl chloride (0.204 mol, 30.8 g). This mixture was stirred for 18 hrs at 20° C. after which time it was poured into 500 ml water, the organic layer separated, washed with water (2×100 ml), brine (100 ml), dried with MgSO4 and concentrated. Resulting crude oil was purified on 400 g silica (EtOAc/Hexanes) yielding 35.0 g (88%) of 1-[(1,1-dimethylethyl)(dimethyl)silyl]-3-methyl-2-pyrrolidinone a clear oil. LCMS (ESI+)=214 m/z (MH+). 1H NMR (400 MHz, CDCl3) δ 3.40-3.25 (m, 2H), 2.50-2.40 (m, 1H), 2.30-2.20 (m, 1H), 1.70-1.60 (m, 1H), 1.20-1.18 (d, 3H, J=7.06 Hz), 0.95 (s, 9H), 0.29-0.27 (d, 6H, J=6.70 Hz).
Reaction SMILES: [O:1]1[CH2:12][C@@H:2]1[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH3:13]>CCO.CO.[OH-].[NH4+]>[NH2:13][CH2:12][C@@H:2]([OH:1])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: NC[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of (2R)-benzyl 2-epoxypropyl ether, 6 (21.0 g, 0.128 mol) in EtOH (100 mL) was added slowly to a solution of 7.0 M ammonia in MeOH (100 mL) and 28% aq. ammonium hydroxide (210 mL) at rt. The reaction vessel was tightly capped and stirred at rt for 23 h. The completed reaction was concentrated in vacuo, and the crude product was azeotroped to dry twice with toluene (100 mL) to provide (R)-1-amino-3-(benzyloxy)propan-2-ol, 23 (23 g) as waxy solid containing approximately 15% of dimer. The crude was used for next reaction without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]3[CH:19]3[CH2:20][CH2:21]3)=[CH:13][C:12]=1[F:17])[CH2:27]2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: Clc1cccc2c1CNC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cn(C2CC2)c2nc(N3Cc4cccc(Cl)c4C3)c(F)cc2c1=O
Yield: 18.8 %

Procedure:
310 mg of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 660 mg of 4-chloroisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in the same manner as in Example 107 to produce 75 mg of 7-(4-chloro-2- isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1>>[CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:32][CH:31]=2)[CH:3]=1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: COC(=O)Cn1c(C)cc(Cc2ccc(C(F)(F)F)cc2)c([N+](=O)[O-])c1=O

Procedure:
This compound is prepared from 5.58 g (14.9 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate and 5 g (20.9 mmol) of [4-(trifluoromethyl)-phenyl]methyl bromide according to the method described in Example 1.5.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-:14].[K+].O.Cl>CS(C)=O>[OH:14][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Chloro-2-nitrobenzoic acid (100 g) in 800 ml dimethylsulfoxide was treated with 112 g powdered KOH with cooling, 170 ml anhydrous alcohol added and the mixture stirred 2 hours at 25° and then left overnight. The mixture was kept at 28° for about 8 hours, then overnight at 0°, warmed to room temperature and 3.5 liters of water added. The mixture was acidified with HCl, 1 kg NcCl added and extracted with ethyl acetate. The extract was washed with water, dried, 50 g KHCO3 in 500 ml water added, diluted to 2 liters, and the ethyl acetate blown off with a stream of nitrogen. The solution was acidified and filtered to give 56 g product, m.128-30°.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[C:11]([OH:12])=[CH:10][C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:8]([F:26])[CH:7]=1>C(N(CC)CC)C.C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:4])[O:12][C:11]1[CH:10]=[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[N:15]([CH3:24])[C:14]2=[O:25])[C:8]([F:26])=[CH:7][C:6]=1[Cl:5]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
0.51 g of methyl isocyanate and subsequently one drop of triethylamine are added at room temperature while stirring to a solution of 2.00 g of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 20 ml of methylene chloride. The reaction mixture is stirred for one hour and evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using diethyl ether-n-hexane (2:1) as the eluent. There is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenyl methylcarbamate, 1H-NMR (CDCl3, 400 MHz): 7.33 ppm (d,1H), 7.24 ppm (d,1H), 6.34 ppm (s,1H), 5.21 ppm (q,1H), 3.54 ppm (d,3H), 2.88 ppm (d,3H).
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH2:5]([O:7][SiH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH3:6]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Ir].[Ir].CC1C=CC(C)=CC=1>[Cl:4][CH2:1][CH2:2][CH2:3][Si:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:7][CH2:5][CH3:6]
Reactant: C=CCCl
Reactant: CCO[SiH](OCC)OCC
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cl-]
Solvent: C1=CCCC=CCC1
Solvent: Cc1ccc(C)cc1
Product: CCO[Si](CCCCl)(OCC)OCC
Temperature: 80 °C
Yield: 83 %

Procedure:
In a minilab pressure reactor of the TINYCLAVE type (BUECHI) with a capacity of 25 ml, 4 g of p-xylene, 4.2 g (0. 055 mol) of allyl chloride and 8.2 g (0.05 mol) of triethoxysilane were mixed intensively with 0.16 mg (10-3 mol %) of chloro-(1,5-cyclooctadiene)iridium(I) dimer at room temperature for one hour. The reaction mixture was then heated at 80° C. for 2 hours in a thermostat. Analysis by gas chromatography gave a product yield of 83% of 3-chloropropyltriethoxysilane.
Reaction SMILES: C[O:2][C:3](=[O:50])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[C:28]([O:30]CC3C=CC=CC=3)[C:27]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:26][C:25]=2[CH2:45][CH3:46])[C:12]=1[CH2:47][CH2:48][CH3:49]>C(Cl)(Cl)Cl>[CH2:47]([C:12]1[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[C:28]([OH:30])[C:27]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:26][C:25]=2[CH2:45][CH3:46])=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:50])=[O:2])[CH2:48][CH3:49]
Reactant: CCCc1c(OCCCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)cccc1Oc1ccccc1C(=O)OC
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCCCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)cccc1Oc1ccccc1C(=O)O

Procedure:
2-[2-Propyl-3-[5-[2-ethyl-4-(4-fluorophenyl)-5-(phenylmethoxy)phenoxy]pentoxy]phenoxy]benzoic acid methyl ester (3.60 g, 5.32 mmol) was submitted to de-benzylation and hydrolysis. The resulting product was isolated via vacuum filtration as a white crystalline solid: mp 65° C. (dec); NMR (CDCl3) 8.25 (dd, J=7.9, 1.7 Hz, 1H), 7.44 (m, 3H), 7.18 (m, 4H), 6.97 (s, 1H), 6.80 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 6.54 (s, 1H), 5.15 (bs, 1H, —OH), 4.10 (t, J=6.1 Hz, 2H), 4.05 (t, J=5.6 Hz, 2H), 2.61 (m, 4H), 1.93 (m, 4H), 1.75 (m, 2H), 1.54 (hextet, J=7.4 Hz, 2H), 1.18 (t, J=7.4 Hz, 3H), 0.89 (t, J=7.3 Hz, 3H); MS-FD m/e 572 (p); IR (CHCl3, cm−1) 3350 (b), 2965, 1739, 1605, 1496, 1455, 1238, 1108.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=3)[CH:39]=[CH:40][C:41]=2[OH:42])=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[O:42][C:41]1[CH:40]=[CH:39][C:38]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:50])([F:51])[F:52])[CH:44]=2)=[CH:37][C:36]=1[C:33]1[CH:34]=[CH:35][N:30]=[N:31][CH:32]=1)#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(-c4cccc(C(F)(F)F)c4)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.7 %

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 19, 206 mg, 0.474 mmol) and 3-pyridazin-4-yl-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 3, 150 mg, 0.474 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (196 mg, 1.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with a 1M aqueous solution of sodium hydroxide whereupon a fine precipitate formed. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as an oil (380 mg, 111%, contains residual dimethylsulfoxide). The material was used without purification in the next step.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].[CH2:10]([N:17]=[C:18]=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:3][C:18](=[O:19])[NH:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CN(C)N
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)CN(C)NC(=O)NCc1ccccc1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
According to the procedure described in the synthesis method of Compound V-1 with the modification that the reaction was carried out overnight, ethyl 2-(1-methylhydrazinyl)acetate (Compound XV-2) 10 ml (76 mmol) was reacted with benzyl isocyanate 11.1 g (83.3 mmol) to obtain the title compound 15.2 g (76%).